Integrated Assessment of Circulating Cell-Free MicroRNA Signatures in Plasma of Patients with Melanoma Brain Metastasis.

Yoshiaki Shoji,Kevin D Tran,Hunter Cole,Rebecca Gross,Matias A Bustos,Dave S B Hoon,Daniel F Kelly,Linh T Tran,Tomohiro Murakami,Selena Y Lin,Christine L Boley,Steven O’Day,Negin Rahimzadeh

doi:10.3390/cancers12061692

Yoshiaki Shoji, Kevin D Tran + Show 11 more

Open Access

https://doi.org/10.3390/cancers12061692

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Journal: Cancers	Publication Date: Jun 25, 2020
Citations: 18	License type: CC BY 4.0

Affiliation: Saint John's Health Center

Abstract

Primary cutaneous melanoma frequently metastasizes to distant organs including the brain. Identification of cell-free microRNAs (cfmiRs) found in the blood can be used as potential body fluid biomarkers for detecting and monitoring patients with melanoma brain metastasis (MBM). In this pilot study, we initially aimed to identify cfmiRs in the blood of MBM patients. Normal donors plasma (healthy, n = 48) and pre-operative MBM patients’ plasma samples (n = 36) were compared for differences in >2000 microRNAs (miRs) using a next generation sequencing (NGS) probe-based assay. A 74 cfmiR signature was identified in an initial cohort of MBM plasma samples and then verified in a second cohort of MBM plasma samples (n = 24). Of these, only 58 cfmiRs were also detected in MBM tissues (n = 24). CfmiR signatures were also found in patients who have lung and breast cancer brain metastasis (n = 13) and glioblastomas (n = 36) compared to MBM plasma samples. The 74 cfmiR signature and the latter cfmiR signatures were then compared. We found a 6 cfmiR signature that was commonly upregulated in MBM plasma samples in all of the comparisons, and a 29 cfmiR signature that distinguishes MBM patients from normal donors’ samples. In addition, we assessed for cfmiRs in plasma (n = 20) and urine (n = 14) samples collected from metastatic melanoma patients receiving checkpoint inhibitor immunotherapy (CII). Pre- and post-treatment samples showed consistent changes in cfmiRs. Analysis of pre- and post-treatment plasma samples showed 8 differentially expressed (DE) cfmiRs that overlapped with the 35 cfmiR signature found in MBM patients. In paired pre-treatment plasma and urine samples receiving CII 8 cfmiRs overlapped. This study identified specific cfmiRs in MBM plasma samples that may potentially allow for assessment of melanoma patients developing MBM. The cfmiR signatures identified in both blood and urine may have potential utility to assess CII responses after further validation.

Highlights

Cutaneous melanoma is one of the most aggressive metastatic solid tumors, with an increasing incidence over the last decade [1]
We demonstrated that the cell-free microRNAs (cfmiRs) signature detected in the melanoma brain metastasis (MBM) patients overlap with the cfmiR found in pre-treatment plasma samples from metastatic melanoma patients receiving checkpoint inhibitor immunotherapy (CII)
There are limited analyses published for cfmiR profiling of large cohorts of plasma and serum samples taken from normal healthy donors [43]

Summary

Introduction

Cutaneous melanoma is one of the most aggressive metastatic solid tumors, with an increasing incidence over the last decade [1]. Melanoma brain metastasis (MBM) can be lethally aggressive often remains dormant in early stages and clinically undetectable [4]. Have significantly improved survival outcomes for metastatic melanoma patients [5,6]; early detection of MBMs remain a key factor for the implementation of treatment regimens such as: targeted therapy, CII, radiological, and surgical interventions [5,7]. Until now, elevated serum lactate dehydrogenase (sLDH) levels are the only validated independent diagnostic blood biomarker for the American Joint Committee on Cancer (AJCC) stage IV melanoma patients, but often sLDH does not translate into meaningful clinical information that can be used for deciding patients’ therapeutic treatments [9,10]

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